The second von Willebrand type A domain of cochlin has high affinity for type I, type II and type IV collagens

Nagy, Ilona; Trexler, Mária; Patthy, László

doi:10.1016/j.febslet.2008.10.050

Cited by 23 publications

(19 citation statements)

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“…4C). Collectively, our results extend previous findings (35) and indicate a model in which the different affinities of collagen IV and collagen VII to the cochlin VWFA domains establish directionality of cochlin in the conduits, and position the cochlin LCCL domain toward the conduit lumen (Fig. 4D).…”

Section: Collagen VII Physically Interacts With the Innate Immune Actsupporting

confidence: 78%

“…The released LCCL domain activates macrophages and neutrophils, stimulating bacterial clearance (16). Cochlin was also of particular relevance as it directly interacts with collagens (35). Importantly, spleens from RDEB mice displayed elevated aggrecanase-1 and -2 expression (SI Appendix, Fig.…”

Section: Collagen VII Physically Interacts With the Innate Immune Actmentioning

confidence: 99%

“…Cochlin has one LCCL domain and two VWFA domains; the C-terminal VWFA2 domain has been shown to interact with collagens including collagen IV (35). We cloned and expressed the LCCL, VWFA1, and two domains (SI Appendix, Fig.…”

Section: Collagen VII Physically Interacts With the Innate Immune Actmentioning

confidence: 99%

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Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.collagen VII | innate immunity | bacteria | recessive dystrophic epidermolysis bullosa | cochlin

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Section: Collagen VII Physically Interacts With the Innate Immune Actsupporting

confidence: 78%

Section: Collagen VII Physically Interacts With the Innate Immune Actmentioning

confidence: 99%

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Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Diminished clearance of misfolded cochlin is believed to be the mechanism by which deafness associated with inner ear deposits in DFNA9 develop (Yao et al 2010). Additionally the second von Willebrand domain within cochlin has been shown to interact with extracellular matrix proteins, collagen in particular (Nagy et al 2008). We do not know if misfolded mutant cochlin also plays a role in the development of deposits within the middle ear of DFNA9 through interaction with extracellular matrix proteins; further study is warranted to specifically investigate this point.…”

Section: Discussionmentioning

confidence: 99%

Extralabyrinthine Manifestations of DFNA9

McCall

Linthicum

O’Malley

et al. 2010

JARO

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DFNA9 is an autosomal dominant cause of nonsyndromic adult-onset sensorineural hearing loss with associated variable vestibular dysfunction caused by mutations in the COCH gene. DFNA9 has previously been characterized by the presence of unique histopathologic features limited to the cochlear and vestibular labyrinth. This report describes newly discovered extralabyrinthine findings within the middle ear in DFNA9 and discusses their implications. The histopathologic anatomy of extralabyrinthine structures was reviewed in 12 temporal bones from seven individuals with DFNA9 and compared with agematched controls. All temporal bones with DFNA9 had abnormal deposits within the tympanic membrane, incudomalleal joint, and incudostapedial joint. Hematoxylin and eosin stain and Movat's pentachrome stain both revealed different staining patterns of the extralabyrinthine deposits compared with the intralabyrinthine deposits suggesting that the composition of the deposits varies with location. The deposits within the tympanic membrane resembled cartilage morphologically and stained positively for aggrecan, an extracellular matrix protein found in cartilage. However, the cellular component of the tympanic membrane deposits did not stain with immunomarkers for chondrocytes (s100 and connective tissue growth factor). These novel findings in DFNA9 have implications for the phenotypic expression of the disorder and the clinical workup of adult-onset sensorineural hearing loss.

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“…The deduced amino acid sequence of cochlin contains a signal peptide in its N terminus, followed by a region homologous to a domain in the FCL domain (factor C of Limulus; also named the LCCL domain for Limulus factor C/Coch-5b2/Lgl1), a short intervening domain, and two von Willebrand factor A-like domains separated by a second short intervening domain. The von Willebrand factor A-like domain is known to function by interacting with extracellular matrix proteins such as collagen (6). The LCCL domain is a novel fold consisting of a central ␣-helix wrapped on two sides by irregular secondary structures that include eight short ␤-strands stabilized by two pairs of disulfide bonds (7).…”

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confidence: 99%

Role of Protein Misfolding in DFNA9 Hearing Loss

Yao

Zhu

et al. 2010

Journal of Biological Chemistry

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Mutations in the COCH (coagulation factor C homology) gene have been attributed to DFNA9 (deafness, autosomal-dominant 9), an autosomal-dominant non-syndromic hearing loss disorder. However, the mechanisms responsible for DFNA9 hearing loss remain unknown. Here, we demonstrate that mutant cochlin, the protein product of the COCH gene, forms a stable dimer that is sensitive to reducing agent. In contrast, wild-type (WT) cochlin may form only dimers transiently. Interestingly, the presence of mutant cochlin can stabilize WT cochlin in dimer conformation, providing a possible mechanism for the dominant nature of DFNA9 mutations. Furthermore, the expression of mutant cochlin eventually induces WT cochlin to form stable oligomers that are resistant to reducing agent. Finally, we show that mutant cochlin is cytotoxic in vitro and in vivo. Our study suggests a possible molecular mechanism underlying DFNA9 hearing loss and provides an in vitro model that may be used to explore protein-misfolding diseases in general.Protein misfolding is a fundamental mechanism underlying multiple chronic neurodegenerative diseases, including Alzheimer disease, Huntington disease, and prion disease, which have been called collectively the conformational diseases to emphasize the role of aberrant protein conformations in the clinical manifestation of the diseases (1). Mutations of different genes involved in these diseases have been shown to lead to oligomerization and aggregation of corresponding proteins to form amyloid. The conformational transition that leads to the formation of amyloid requires misfolding of native protein structure and intermolecular bonding. However, we still understand very little about the conformational transition processes from the misfolded state to the aggregated state, as this transition for most conformational disease-associated mutant proteins explored so far is both rapid and heterogeneous.Point mutations in the COCH (coagulation factor C homology) gene are responsible for an autosomal-dominant non-syndromic hearing disorder termed DFNA9 (deafness, autosomaldominant 9) (2). DFNA9 is characterized by adult-onset, progressive neurosensory hearing loss with vestibular dysfunction. Pathological studies of the temporal bones from affected individuals have shown remarkable degeneration of neuroepithelial cells, including both fibrocytes and neurosensory cells, and the accumulation of abundant acellular eosinophilic deposits throughout the auditory and vestibular systems (3, 4). However, the mechanism responsible for the degeneration and hearing loss in DFNA9 syndrome remains unknown.The amino acid sequence of cochlin, the protein product of the gene COCH, is highly conserved in mammals (5). The deduced amino acid sequence of cochlin contains a signal peptide in its N terminus, followed by a region homologous to a domain in the FCL domain (factor C of Limulus; also named the LCCL domain for Limulus factor C/Coch-5b2/Lgl1), a short intervening domain, and two von Willebrand factor A-like domains separated by a se...

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The second von Willebrand type A domain of cochlin has high affinity for type I, type II and type IV collagens

Cited by 23 publications

References 23 publications

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Extralabyrinthine Manifestations of DFNA9

Role of Protein Misfolding in DFNA9 Hearing Loss

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